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Ron Davis gets a win but will he ever be given the chance to bring his core disrupting technologies to ME/CFS?

ME/CFS Moment

An ME/CFS Moment: an indication that the ME/CFS field is moving to the next level.

An ME/CFS Moment: something unexpected happens that indicates the tide is rising for the ME/CFS field. This could include something like a big grant opportunity for the field from the NIH or an institution deciding it needs to revamp its ME/CFS program (see below).

 

A Possible ME/CFS Moment – something unexpected happens that may indicate the tide is rising for the ME/CFS field. This could include a new grant (see below), or an increase in a researchers or clinics workload. It might have happened anyway – but it could be a sign.

Health Rising recently highlighted two potential ME/CFS moments: Dr. Natelson’s multiple NIH grants and a very busy Bateman Horne Center.  MEAction recently had the purest ME/CFS moment yet: the most respected and influential clinical care group in the U.S. – the Mayo Clinic at Rochester  – reached out to MEAction to help them revamp their ME/CFS program. MEAction reported that their “detailed, respectful and frank conversations” were met with “enthusiasm and receptiveness”. When the Mayo Clinic – whose name is basically dirt in the ME/CFS community –  changes its spots, ME/CFS’s star is clearly rising.

Now Ron Davis may be having one as well. If he is – it’s about time. Even having a hamstrung Ron Davis operating on a shoestring budget is a gift. Giving him the funds he needs to really dig into ME/CFS would really be something. This nice grant won’t do that but it is a start.

Davis is nothing if not an original and creative thinker. We knew that – he was called one of the most innovative creators of the 20th century, has received many awards, and is presumed to be on the shortlist for a Nobel Prize. Time and time again, outside and inside this field, he’s gone down paths all his own.

Severe ME/CFS Illness Project Pays Off

Ron Davis

Inside and outside of ME/CFS, Ron Davis’s career has been characterized by creativity

The Open Medicine Foundation’s Severe ME/CFS data project is a good example of that. People with severe ME/CFS were being virtually ignored when Davis, citing the need to go where the disease was shining brightest, launched the deepest molecular probe into any ME/CFS patients ever – spending upwards of $100,000 per severely ill patient. It was a creative, as well as daring, “big picture” approach to studying ME/CFS.

The study findings are undergirding much of the Davis team’s work. His work on the nanoneedle, Robert Phair’s Metabolic Trap hypothesis, Phair’s itaconate pathway hypothesis, and the recent grant award all came out of the Severe Illness study, and all are novel approaches that no one in this field but Davis and his team could have come up with. So is the big Department of Defense (DOD) $1.6 million grant he and Laurel Crosby recently received.

Hair Analysis!

Davis’s almost futile attempts to get government funding (and his disdain for his reviewers) are well known. He and Mark Davis did get a big immune grant but, in truth, that one seemed almost too good a match for the NIH to fail. Otherwise, the pickings have been slim, indeed.

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That makes Davis and Laurel Crosby’s recent big win all the more interesting. If one was to draw up a list of subjects that were least likely to get funded, I imagine that hair analysis – long associated with alternative health practitioners – would be near the top. I was not able to find any ME/CFS study that has employed hair analyses in order to better understand ME/CFS patients’ pathophysiology.

Managanese

The hair analyses produced a surprise! Low manganese levels were commonly found. Low copper and selenium levels were also found.

Davis explained that hair analyses have always been a bit suspect because high readings can reflect anything from pollution to the ingredients in shampoo that has fallen on the hair. (One of Davis’s findings – high levels of uranium in some patients’ hair – were traced to contaminated well water.)

The major finding, though, was consistently low levels of manganese as well as low levels of copper and selenium. Those low levels must reflect something that’s going on in the body. Davis used mass spectrometry which, incidentally, is cheap and easy to do – and just never done in ME/CFS.

Manganese deficiency is nothing to play around with and has some interesting potential tie-ins with ME/CFS. Many enzymes need manganese to function. You can’t, for instance, process pyruvate – a key player in energy production – without sufficient levels of manganese. Low copper and selenium levels could also play a role in ME/CFS.

Davis clicked off a number of possibilities: the minerals are not being absorbed in the first place and the kidneys are secreting them. Balky manganese transporters may be involved. Or the mineral may just not get into the hair for some reason. It’s going to take some work to figure out. Blood work is needed to assess manganese blood levels.

Along the line, a lot of blood chemistry and genetics is going to be done – and that will have the add-on benefit of giving Davis a much clearer look at the biochemistry and genetics of ME/CFS. The patient samples – which will be sent through the mail – are going to be gathered using a new type of technology called Tasso, which allows you to draw blood without using needles.

Let’s not forget the role ME/CFS advocacy played in making this study possible. It took a lot of work over several years to get ME/CFS back into the CDMRP (Congressionally Directed Medical Research Programs) program. Our track record is still not very good there – many grants have gone in and only a few have come out funded – but we have had some successes – and every grant win increases our knowledge of ME/CFS.

An Extraordinary Run at the NIH

Davis has been very open about the shoddy treatment he believes his ME/CFS grants have received at the NIH. His upset is understandable. This study – funded by the Department of Defense, not the NIH – is the kind of long-term well-funded study that used to be a piece of cake for Davis.

NIH funding ME/CFS

Prior to focusing on ME/CFS, Davis was so successful at getting NIH grants that at times he was probably receiving more NIH funding than the entire ME/CFS field.

Outside of ME/CFS Davis, has had an extraordinary run of success at the NIH. Over the past 30 years, he’s received 12x $2 million; 7x $5 million; 3x $7 million; and 13x $8 million NIH grants intermixed with dozens of smaller grants. Those money totals are per year by the way.

That’s well over $150 million in grants. It appears that for a good bit of the time, Davis was probably getting more NIH funding for his genetic and technology work than the NIH was providing for the entire ME/CFS field.

Contrast that track record with the one @$700,000/year NIH grant he and Mark Davis have received to study ME/CFS over the past five years and you can see why Davis is so frustrated. Davis told me that a recent grant application for an Abilify study was denied because the initial reviewer believed ME/CFS was simply depression and that was it for that.

He is not alone. Ron Tompkins also had a spectacular grant run at the NIH (10x $1 million; 9x $2 million; 2x $3 million; 5x $7 million; 6x $8 million) until he, too, ran into an ME/CFS block there. Tompkins felt his chances were so low with the NIH that he decided to direct all his grant applications to the DOD – most of which were rejected.

The loss of significant federal funding produces costs in so many ways, one of which involves continuity of staff. In a recent call, Davis talked about how hard it was to engage in long-term projects without government support. He noted that he’d lost two ME/CFS research assistants to industry in the past year.

The biggest loss, though, in that area, was surely the nanoneedle inventor, Rahim Esfandyarpour, to a University that offered him a tenure-track position. That tenure-track position came with a catch, though: Esfandyarpour would have to attract NIH funding to get it. Donations to work on the nanoneedle wouldn’t work. After the NIH – which actually funded the development of the nanoneedle for cancer – refused to fund it for ME/CFS the exciting nanoneedle work was left mostly on the back-burner.

Threading the Needle: Nanoneedle Scores Big in First ME/CFS Test

Davis did get a new and better nanoneedle machine, but it still needs to be redesigned. Esfandyarpour is redesigning it, but given his many other responsibilities – and his lack of NIH funding – that will take time.

This rare big grant win (well, a decidedly small grant by Davis’s standards – but a big grant for this field), though, provides some hope that we’re in the midst of an ME/CFS “moment”.

The Metabolic Trap

The metabolic trap is another case of Davis striking out on his own – and a reminder that he’s on the lookout for an overarching explanation for ME/CFS. The trap hypothesis, which also came out of the severe ME/CFS patient data, emerged when Robert Phair, an engineer, biologist, and kinetic modeler, came across some data that didn’t make sense to him.

The Metabolic Trap Shines During the Symposium on the Molecular Basis of ME/CFS at Stanford

 

Phair was looking for something associated with an infection that could cause a system to suddenly “flip” into a new state which would be difficult to escape from, and would be able to affect multiple systems, and cause something as devastating as ME/CFS.

He found it in the ID01/ID02 enzyme system responsible for breaking down the high levels of tryptophan produced during an infection. We don’t need or want high tryptophan levels. What we want from tryptophan is the kynurenine that it gets converted into.

The ID01 enzyme steps in to break tryptophan down, but at high enough tryptophan levels the enzyme can get overwhelmed. In rides the cavalry – ID02 – and breaks the tryptophan down. What if ID02 isn’t working so well, though, and tryptophan levels continued to rise?

High tryptophan levels mean high serotonin levels in the brain – something that could potentially cause just about every symptom in ME/CFS. (The Cortene hypothesis – which showed up shortly before the Metabolic Trap hypothesis – also proposes high brain serotonin levels are causing ME/CFS). Plus, with low kynurenine levels, you lose a pretty nifty immune regulator and autoantibody controller. Both the Trap and the Cortene hypothesis have the potential to explain much.

Cortene II: A New Drug & A New Hypothesis For Chronic Fatigue Syndrome (ME/CFS)

Phair’s mathematical models indicated that high cellular tryptophan levels over time could produce a devastating situation that was almost impossible to recover from. Phair and Davis next found that the genetic requirements for the trap did appear to exist in people with ME/CFS, and a preliminary sample of ME/CFS patients’ cells suggested that the trap did exist.

Yeast!

Since then, Phair and Davis have been methodically testing the trap. They recently found that the metabolic trap can be sprung in yeast; i.e. it’s no longer a hypothetical construct – if tryptophan is allowed to rise in a cell, it can spring the trap.

Yeast

When it comes to assessing basic processes yeast cells are invaluable: they have a nucleus and can easily be genetically manipulated to mimic human cells. (Frank Roberton CC – Wikimedia Commons)

You might think yeast! What does yeast have to do with humans? Well, yeast is no laughing matter in research circles. Because yeast cells share many basic biological properties with human cells, and because its genome is so well known, researchers often go to yeast to investigate very basic cellular properties and to test drugs.

It’s easy for researchers to insert human genes into yeast and then probe, test, and manipulate them – essentially mirroring in a yeast cell what happens in a human cell.

Back in the 1990s, 600 researchers from over 100 labs worked to sequence the first yeast genome. At the time, it was the largest genome ever sequenced, and yeast still occupies a prominent place in research today. In 2017, the first 3-dimensional representation of the yeast genome was produced, and yeast is now being used to develop more effective antifungal drugs (including Candida albicans), to identify longevity genes, and understand mitochondrial diseases, among many others.

Davis probably knows the yeast genome better than anyone else. He’s had many yeast grants – among them a $5 million grant to sequence the yeast genome using a new, very rapid, low-cost technique. The first thing his biochemistry page at Stanford highlights, in fact, is his yeast/genome work. It may be what he’s best known for.

First, Davis produced a yeast cell that could process tryptophan – a central element of the trap hypothesis. For a while, the yeast could handle the tryptophan buildup, but when it reached a certain level, the yeast fell into a kind of stasis state and was unable to grow. The trap had been sprung – and an ME/CFS-like state had emerged.

Davis has started to test FDA-approved drugs in his metabolic trap-engineered yeast. Not just some FDA-approved drugs – all FDA-approved drugs are being tested to see if they can unspring the metabolic trap in yeast and allow it to grow again.

The “Poster Child of Metabolic Reprogramming”: the Itaconate Pathway

Itaconate provides another example of the different thrust that Phair and Davis are taking in ME/CFS. Called the “poster child of metabolic reprogramming” itaconate is produced during the TCA (or Krebs or citric acid – take your pick) mitochondrial cycle. It was Naviaux that alerted us to the role the mitochondria play during an infection – and during an infection, the itaconate pathway gets turned on in immune cells (and probably others).

Aconitate Krebs cycle

Itaconate blocks aconitate from entering the Krebs cycle (see the Krebs cycle at about two o’clock or upper right part of the circle.)

There, it produces a shunt that blocks compounds from entering the TCA cycle – thus reducing the cells’ ability to produce ATP – thus resulting in fatigued or exhausted (or hypometabolic or Dauer-like – take your pick) immune cells. Immune cell exhaustion – particularly NK and T-cells – may be present in ME/CFS, but this process could also apply to muscle cells and help explain why they get exhausted so quickly. A long-lived and hyperactive itaconate pathway could also contribute to the fat-burning problem and the strange case of the disappearing ammonia, which may exist in ME/CFS as well.

Why would a cell turn off its own energy? Perhaps to hunker down and wait out the threat (?). Perhaps to induce “sickness behavior” and get us to lie down, reduce our contact with others, and stop spreading infection.

Phair is modeling the mitochondria to see what could turn on/off this pathway and Davis said he was confident they would be able to assess the itaconate pathway in ME/CFS patients’ cells. That is, once they replace their latest loss to industry – another researcher recruited away.

BH4

The severe ME/CFS data study also prompted Davis to put in a grant to study tetrahydrobiopterin (BH4, sometimes THB). It turns out that some people had a mutation in BH4 synthesis. BH4 is a vital cofactor for numerous enzymes in the body, including those involved in the formation of nitric oxide (NO – blood vessels), and the key neurotransmitters dopamine, serotonin, and epinephrine.

A Common Thread

Biochemistry focus

Davis brings a strong biochemical focus to ME/CFS research. (Image from Biochemistry Principles by Moran, Horton, etc.)

You can see a common thread emerging – biochemistry: “the study of chemical processes within and relating to living organisms”.  The professor of biochemistry and genetics at Stanford Davis has a Ph.D. in biochemistry. Davis, who is superb at visualizing biochemical reactions, probably goes to sleep with visions of biochemical reactions dancing in his head.

The Gist

  • Described as a “frequent provider of core disruptive technologies”, Ron Davis’s career both inside and outside of ME/CFS has been characterized by innovation and creativity.
  • The Open Medicine Foundation’s Severe ME/CFS project is a typical example of Davis’s often daring approach to this disease. Upwards of $100,000 per patient allowed Davis and others to dig deeper into their molecular biology than ever before. Its findings have laid the groundwork for much of the work Davis is engaged in now.
  • That includes the DOD grant Davis and Laurel Crosby just received in which they used hair analysis to uncover a common deficiency of manganese as well as copper and selenium.
  • Manganese plays a critical role in many enzymatic reactions including those involved in energy production. As an added bonus the study will provide the opportunity to gather a wide range of biochemical and genetic data on a large group of ME/CFS patients.
  • Davis and Phair have uncovered two unique ways (the Metabolic Trap hypothesis and itaconate pathway) which could explain how an infection could rewrite vital metabolic processes – potentially leading to ME/CFS.
  • The Metabolic Trap hypothesis has evolved from its beginnings as a genetic query, to include a mathematical modeling approach, analyses of ME/CFS patients’ cells, and a duplication of the trap in yeast. Now Davis is using yeast cells to test FDA-approved drugs to see if he can “unspring” the trap.
  • Davis’s focus on biochemistry brought the metabolic trap hypothesis, the itaconate pathway work, and now work on BH4 to the ME/CFS field. His technology work has brought the nanoneedle, red blood cell deformability, neutrophil flow, a sweat crash test, and other possibilities to the field.
  • Bringing new and unusual possibilities to a field is nothing new for Davis who had an extraordinary run that garnered over $150 million in NIH grants prior to entering the ME/CFS field. Since then, though, he’s had difficulty getting federal funding.
  • Time will tell if the DOD win constitutes a real ME/CFS moment; i.e.; a sign that ME/CFS is being accepted and recognized in places it was rejected before. Time will also tell if Davis will ever be given the opportunity to bring the “core disruptive technologies” he’s famous for to the ME/CFS field. Let’s hope he gets that chance.

His biochemical slant is one reason why his ME/CFS work is so distinct. It’s also why he’s so jazzed at the hair analysis grant – which will give him an ample opportunity to plunge into ME/CFS patients’ biochemistry.

The other thread is technology. Davis has been described as “a frequent provider of disruptive core technologies“.

Besides his genetic work that helped lay the groundwork for Genome Project Davis’s forte has been developing low-cost, effective medical devices. He’d love to develop a cheap, effective diagnostic test for ME/CFS. A number of possibilities exist.

There’s the red blood cell deformability tool that’s being developed that he believes might cost a dollar a test to produce. After finding that neutrophils are also having trouble flowing properly in ME/CFS patients’ blood a tool to measure neutrophils is a possibility as well. The idea that neutrophils – which have hardly ever been studied in this disease – might actually constitute a diagnostic test –  highlights an important fact: the first diagnostic test for ME/CFS could come from a totally unforeseen corner.

Nothing demonstrates that better than the nanoneedle which uses electrical impedance to assess cellular activity. We don’t know what biological factor it’s picking up on; i.e. we don’t know what it’s telling us about ME/CFS but we do know that it produces highly consistent results. It’s invariably able to differentiate people with ME/CFS from healthy controls.

Nor do we associate ME/CFS with significant eye problems but Chris Armstrong’s early work suggests that ME/CFS patients’ eyes track movements might actually be diagnostic for this disease.

Davis’s ideas seem to know no bounds. He’s working with a former student – now a professor at UCLA – to assess the content of sweat in hopes of developing a wearable device that could tell a person with ME/CFS that they’re pushing their limits and are going to crash if they go much further. We have no PEM warning device right now. Davis talked about a student who became bedbound with ME/CFS and wondered whether the disease was perpetuating itself by her crashes. In what must have been a very disciplined effort she made sure she didn’t crash for a year – and eventually fully recovered.

Time will tell if the “core disruptor” will be given the opportunity to unleash his creative gifts on the ME/CFS field as well. Davis did say that he put in four grant applications last year and that the comments, this time, he felt had some validity; i.e. his grant applications were being taken more seriously – a good sign.

Time will also tell if Davis is indeed having an “ME/CFS moment”; that is if the wind is finally catching his ME/CFS sails – sending more funding his way.

Given the track record he’s built over his long career, and his many interesting ideas, one would hope that would be a strong wind indeed.

 

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